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The role of the formyl-peptide receptor in multi-organ fibrosis mechanisms
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Dissertation
The role of the formyl-peptide receptor in multi-organ fibrosis mechanisms
2016
Overview
Mitochondrial Damage-associated molecular patterns (mtDAMPs) are an emerging source of endogenous alarmins. N-formylated peptides bind members of the formyl-peptide receptor (FPR) family. From its original role in chemotaxis of immune cells towards sites of infection the part that this G-protein coupled receptor (GPCR) plays in the human body is expanding with expression evident in cells of non-phagocyte origin as well as neutrophils and macrophage. To investigate how FPR1 affects the development of pulmonary fibrosis the bleomycin acute injury in vivo model was employed as its pathogenesis shares features with Idiopathic pulmonary fibrosis (IPF). Transgenic mice lacking functional fpr1 displayed a reduced inflammatory profile and fibrotic phenotype at acute and end-stage endpoints respectively post-bleomycin instillation. In vivo models of fibrosis in different organs such as the liver and kidney there was not the same protective effect with deletion of fpr1 as with acute bleomycin lung injury mechanism. This in turn brought the pathogenesis of the in vivo models into question particularly due to the abundance of fpr1 expression on neutrophils, the first line of defense of the immune system. By depleting neutrophils prior to the bleomycin injury the nature of these myeloid cells in this lung fibrosis model and through evaluation of the inflammatory and fibrotic phases post-instillation it is evident that these cells play a major role in how the disease develops. Translation to the human disease (IPF) was a vital step to elucidate the true role of FPR1 in chronic fibrosis mechanisms. Expression was demonstrated by immunofluorescence in CD45+ leukocytes as well as in isolated fibroblasts. This was corroborated by mRNA levels in primary cultured cells when FPR1 expression was ‘primed’ by inflammatory stimuli such as lipopolysaccharide (LPS). With effects observed in a murine setting and also in primary tissue/cells the FPR1 effect may be microenvironment/neutrophil dependent.
Publisher
ProQuest Dissertations Publishing
Subject
